The organism's degree of behavioral control over stressors is among the most powerful factors in determining the individual's reaction to an encounter with such an event. Organisms that have no control over aversive events to which they are exposed reveal a variety of behavioral and physiological disturbances that do not occur if the organism does have control, even though the stressors are physically identical. Effects that depend on the controllability of the events experienced have been called "learned helplessness" effects. These effects and the theoretical entities said to produce them have been proposed to be important causes of reactive depression, certain instances of failure in school, some psychological aspects of aging, some of the effects of crowding, urban stress, anxiety, etc. Thus it is important to understand the mechanisms by which the controllability/uncontrollability of stesssors alters behavior and physiological functioning. The research proposed here is directed at such an understanding. Moreover, the controllability dimension exerts effects at many different levels and affects numerous systems (behavioral, endocrine, immune, neurochemical). A multidisciplinary approach designed to understand learned helplessness at each of these levels is proposed here, with the long-term goal of a truly integrated understanding of this set of phenomena. Three specific lines of research are proposed. The first centers on the role of controllability in modulating the impact of stressors on the immune system. Here the focus will be on three interrelated questions: a) What is the critical behavioral/psychological dimension of the stress situation that leads to changes in immune function?; b) What is the mechanisms by which this behavioral event(s) alters immune function?; c) What aspects of immune function are actually altered? The second line of research explores the role of the hypothalamo-pituitary-adrenal (HPA) system and central peptide hormones in learned helplessness. Two major questions will be posed. a) Is shock of differing controllability associated with differential activation of central nervous system CRF, beta-endorphin, and ACTH, and peripheral HPA activation?; b) Do the behavioral and neurochemical outcomes of exposure to uncontrollable shock depend on intact HPA function? The final line of research continues the prior work of this laboratory and examines the nature of the behavioral changes produced by uncontrollable stressors, and the involvement of opioid and aminergic mechanisms in these changes.